Cephalosporin antibiotics having various heterocyclic thiomethyl substituents in the 3-position are known. For example, Takano et al., U.S. Pat. No. 3,516,997, describe tetrazolthiol and thiadiazolthiol substituted cephalosporins having a heterocyclic acylamino group in the 7-position; Ryan, U.S. Pat. No. 3,641,021 describes tetrazolthiol and thiadiazolthiol substituted cephalosporins having a mandeloyl or phenylglycyl substituent in the 7-position; Breuer, et al., U.S. Pat. No. 4,110,535, describe certain cephalosporin compounds having a 3-oxopyridazinylthiomethyl substituent in the 3-position; Berges, U.S. Pat. No. 4,107,173, describes cephalosporin compounds having as the 3' substituent a 3-sulfomethyl-1,2,4-triazol-5-ylthiomethyl substituent; Toshiyasu, et al., U.S. Pat. No. 4,103,008, describe cephalosporin compounds substituted in the 7-position by a dioxopiperazine-1-yl-carbonylamino substituent and in the 3-position by a substituted or unsubstituted 1,3,4-thiadiazol-2-ylthiomethyl substituent; Berges, U.S. Pat. No. 4,101,656, describes 7-acylamino substituted cephalosporins having a tetrazolthiomethyl substituent in the 3-position which is substituted with an alkylsulfonamidoalkyl group; Gottstein, et al., U.S. Pat. No. 4,100,346, describe certain o-aminophenylacetamido substituted cephalosporins having a tetrazolthiomethyl substituent in the 3-position which is substituted with a carboxyethyl or carboxypropyl substituent; Numata, et al., U.S. Pat. No. 4,080,498, disclose a 2-aminothiazolacetamido cephalosporin substituted in the 3-position with a heterocyclic thiomethyl group; Dunn, et al., U.S. Pat. No. 3,968,226, describe numerous 3-heterocyclicthiomethyl substituted cephalosporins; Naito, et al., U.S. Pat. No. 4,082,912, disclose 7-acylamidocephalosporins having the fused heterocyclic, (2-carboxyalkyl)-2,3-dihydro-S-triazolo[4,3-b]pyridazin-3-one-6-ylmethyl group in the 3-position; British patent specification No. 1,525,626 describes certain cephalosporin compounds having a 1-carboxymethyl-1H-tetrazol-5-thiomethyl substituent in the 3-position; Dunn, et al., U.S. Pat. No. 3,985,739, describe 7-phenylglycyl or 7-mandeloyl substituted cephalosporins having in the 3-position a 1,3,4- or a 1,2,3-triazolthiomethyl substituent; Naito, et al., U.S. Pat. No. 3,985,738, describe 7-mandelamidocephalosporins having in the 3-position a tetrazolo[4,5-b]pyridazin-6-ylthiomethyl substituent; and Barth, U.S. Pat. No. 3,966,719, discloses cephalosporin compounds wherein the 4-carboxy group is replaced with a tetrazol-5-yl group.
3-Heterocyclicthiol substituted methyl cephalosporins are generally prepared by the displacement of the acetoxy group of a 3-acetoxymethyl-3-cephem, or the halogen of a 3-halomethyl-3-cephem compound, with the desired heterocyclic thiol. Hatfield, U.S. Pat. No. 4,144,391, describes a non-aqueous displacement method for the preparation of 3-heterocyclicthiomethyl substituted cephalosporins.
This invention is concerned with broad spectrum cephalosporin antibiotics which differ structurally from the known cephalosporins. In particular, this invention relates to 7-amino and 7-acylamino cephalosporin compounds substituted in the 3-position of the dihydrothiazine ring with a bis-tetrazolylmethyl group. In particular, the bis-tetrazolylmethyl substituents are the 1-(1H-tetrazol-5-ylmethyl)-1H-tetrazol-5-ylthio group and the isomeric 2-(1H-tetrazol-5-ylmethyl)-2H-tetrazol-5-ylthio group.